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Am J Physiol Heart Circ Physiol 276: H326-H332, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 1, H326-H332, January 1999

SPECIAL COMMUNICATION
New simple methods for isolating baroreceptor regions of carotid sinus and aortic depressor nerves in rats

Takayuki Sato1, Toru Kawada1, Hiroshi Miyano1, Toshiaki Shishido1, Masashi Inagaki1, Ryoichi Yoshimura1, Teiji Tatewaki1, Masaru Sugimachi1, Joe Alexander Jr.2, and Kenji Sunagawa1

1 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan; and 2 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

We developed new methods for isolating in situ baroreceptor regions of carotid sinus and aortic depressor nerves in halothane-anesthetized rats. After ligation of the root of the external carotid artery, the internal carotid and pterygopalatine arteries were embolized with two ball bearings of 0.8 mm in diameter. Bilateral carotid sinus pressures were changed between 60 and 180 mmHg in 20-mmHg steps lasting 1 min each. The sigmoidal steady-state relationship between aortic and carotid sinus pressures in 11 rats indicated the maximum gain of the carotid sinus baroreflex to be -2.99 ± 0.75 at 120 ± 5 mmHg. An in situ isolation of the baroreceptor area of the right aortic depressor nerve could be made by ligation of the innominate, common carotid, and subclavian arteries in 9 rats. Pressure imposed on the subclavian baroreceptor was altered between 40 and 180 mmHg in 20-mmHg steps lasting 1 min each. The sigmoidal steady-state relationship between the aortic depressor nerve activity and imposed pressure showed that the baroreceptor gain peaked at 118 ± 4 mmHg. We established an easy approach to the rat baroreflex and baroreceptor research.

gain; feedback system; open-loop conditions; steady state

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

A USEFUL ANIMAL MODEL for a variety of clinical maladies ranging from hypertension to heart failure, the rat as an experimental animal is very important to cardiovascular research. Its usefulness in molecular-based investigations is also an important advantage. For these reasons, the physiology and pathophysiology of cardiovascular regulation mediated through arterial baroreceptors have been frequently examined in rats under diseased as well as normal conditions (2, 7, 10, 15, 17, 20, 22). Most of such investigations, however, have been performed under closed-loop conditions (7, 10, 17, 22) because of inherent difficulties in the rat in isolating the baroreceptors and in opening the feedback loop. It is important to recognize that analyses of dynamic feedback systems under closed-loop conditions could lead to erroneous conclusions (12). Although a study of the carotid sinus baroreflex in the rat (15) was conducted under open-loop conditions, the method of isolation of the carotid sinuses was not described in detail. To overcome these limitations in the rat, Shoukas et al. (20) developed a new method for isolating the carotid sinus baroreceptor area. They embolized the internal carotid artery and its main branches with custom-made cylindrical rubber plugs introduced into the common carotid artery by means of a custom-made plug injector. Their method, unfortunately, has seldom been used by other investigators because of the skill required in making the special plug and injector.

For studies of baroreceptor transduction properties, the aortic depressor nerve has been used in the rat. Most of the studies were performed under closed-loop conditions and in nonisolated preparations, and the pressure changes imposed on the baroreceptors were produced pharmacologically (7, 18, 23). Our previous study (19), however, showed that accurate and reliable evaluation of baroreceptor function is difficult unless the rate of change in pressure is strictly controlled. Specifically, such preparations lacking strict controllability of the rate of pressure change could result in an erroneous estimation of maximum baroreceptor sensitivity due to the dynamic transduction properties from pressure to nerve activity. The in vitro preparation of the aortic arch and left aortic depressor nerve developed by Brown and co-workers (3-5) solved the problem of the lack of controllability of the rate of pressure change but replaced it with the new in vitro challenge of attempting to preserve the in situ normal configuration of the aortic arch. Failure to meet that challenge could result in an erroneous estimation of the transduction properties (19). Moreover, the in vitro method could not be applied to baroreflex studies (16). Many recent investigators (3, 7, 16), operating under the impression that the baroreceptors of the aortic depressor nerve of the rat were located only within the wall of the aorta, assumed that in situ baroreceptor isolation was impossible without complex surgical procedures such as bypass or cross-circulation techniques as used in dogs (11). However, in 1924, Tello (21), who examined the embryogenesis and development of the aortic depressor nerve in mice and rabbits, concluded that the baroreceptors of the right aortic depressor nerve in the adults were limited to the bifurcation of the innominate artery into the right subclavian and common carotid arteries. He noted that a prototype of the aortic depressor nerve grows nearby and into the fourth brachial (aortic) arch of the embryo. The right fourth brachial arch develops into the root of the right subclavian artery and the distal end of the innominate artery. Nonidez (13), therefore, suggested that the depressor nerve should be named the "aortic" nerve in the embryo but not in the adult.

To overcome these technical limitations and critiques, we developed new simple methods for the in situ isolation of baroreceptor regions of carotid sinus and aortic depressor nerves in the rat. Our methods did not require special materials, tools, or manipulation of the baroreceptor regions.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

The care of animals was in strict accordance with the guiding principles of the Physiological Society of Japan. A total of 20 male Sprague-Dawley rats weighing 280-350 g were used. In each experiment, the rat was first placed in a glass jar where it inspired a mixture of 2% halothane (Fluothane; Takeda Pharmaceuticals, Tokyo, Japan) in oxygen-enriched air for 5-10 min. After induction anesthesia, an endotracheal tube was introduced orally, and the rat was ventilated artificially via a volume-controlled rodent respirator (model 683; Harvard Apparatus, South Natick, MA). In accordance with Ono et al. (17), anesthesia was maintained through use of 1.2% halothane during surgical procedures and 0.6% halothane during data recording. Pancuronium bromide (0.8 mg · kg-1 · h-1 iv) was administered to eliminate spontaneous muscle activity. Arterial blood gases were monitored with a blood gas analyzer (IL-13064; Instrumentation Laboratory, Lexington, MA). For measurement of aortic arch pressure, a 2-Fr catheter-tip micromanometer (SPC-320; Millar Instruments, Houston, TX) was placed in the aortic arch through the right femoral artery. A polyethylene tubing (PE-10; Becton Dickinson, Parsippany, NJ) was inserted into the right femoral vein. For the prevention of dehydration during experiments (7), physiological saline was continuously infused at a rate of 5 ml · kg-1 · h-1 with a syringe pump (CFV-3200; Nihon Kohden, Tokyo, Japan).

Bilateral Isolation of Carotid Sinus Baroreceptor Areas

Surgical procedures. On reaching the tympanic bulla, the internal carotid artery arising from the common carotid artery gives off only the pterygopalatine artery (Fig. 1). The internal carotid artery enters the carotid canal and the pterygopalatine artery enters the posterior lacerated foramen of the skull (18). To expose the bifurcation of the common carotid artery into the external and internal carotid arteries, we made an incision from just under the chin down the midline to the sternal notch and then cut the sternomastoid and omohyoid muscles. Under a surgical operating microscope (Wild M650; Leica, Heerbrugg, Switzerland), the external and internal carotid, occipital, and carotid body arteries were identified. To minimize the invasion and damage of the carotid sinus baroreceptors and nerve, we did not touch any structure such as the ansa hypoglossi bundle, the digastric muscle, or the fat and connective tissue between the external and internal carotid arteries. A fine pair of forceps (model 0202-5/45-PO; Manufactures des Outils Dumont, Montignez, Switzerland) was placed at the root of the bifurcation of the common carotid artery and was plunged into the vascular triangle formed by the external and internal carotid and carotid body arteries. An 8-0 nylon monofilament suture was threaded through the vascular triangle with the pair of forceps and tied around the external carotid artery. The common carotid artery was ligated at the proximal portion. After the distal portion of the common carotid artery was clamped with a bulldog spring clamp (model 18044-23; Fine Science Tools, North Vancouver, BC, Canada), the common carotid artery was immersed in a pool of warm saline. Water immersion prevented air embolism during the following procedures. The vascular wall was incised between the clamped and ligated portion of the common carotid artery. A high-grade stainless-steel ball bearing (E-20; Tsuhaki Nakashima, Amagasaki, Japan) of 0.8 mm in diameter was put into the common carotid artery through the incision with a pair of forceps. In a separate pilot study, we had determined the optimal size of the ball bearing for embolization of the internal carotid and pterygopalatine arteries at their entrances to the skull. Next, the polyethylene tubing (PE-50, Becton Dickinson) that was filled with saline and connected to a glass syringe and to a fluid-filled transducer (DX-200, Viggo-Spectramed) was inserted into the common carotid artery through the incision. After the suture was placed around the common carotid artery where the polyethylene tubing was introduced and temporarily tied, the bulldog spring clamp was released and intracarotid pressure was monitored. The glass plunger was pushed so that the ball bearing was swept away and wedged in either the internal carotid or pterygopalatine artery at the entrance to the skull. During this procedure, the intracarotid pressure given with the glass syringe must not exceed 200 mmHg. Excessive pressure could cause permanent damage to baroreceptors (20). Next, the distal portion of the common carotid artery was clamped again with the bulldog spring clamp, and then the polyethylene tubing was pulled out. The embolization procedure for the other artery was repeated again. Finally, the tip of the polyethylene tubing was advanced into the root of the carotid sinus and was tightly fixed with suture (Fig. 1). The carotid sinus was filled with saline, and carotid sinus pressure was monitored. Using the two ball bearings, we always succeeded in making a watertight chamber of the single carotid sinus region and did not need any additional ball bearings.


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  		Fig. 1.   Schematic illustration of surgical isolation of carotid sinus baroreceptor area. Ansa hypoglossi nerve bundle, glossopharyngeal nerve, and superior cervical sympathetic ganglion are omitted for the sake of simplicity. Internal carotid and pterygopalatine arteries are embolized at the entrance of the skull by 2 ball bearings of 0.8 mm in diameter. a, Artery; n, nerve.

By following these procedures, we succeeded in making watertight chambers of both carotid sinus regions within 1 h from beginning to end. The vagi and aortic depressor nerves were cut bilaterally at the level of the nodose ganglion, while both carotid sinus pressures were controlled at 100 mmHg with a servo-controlled pump system based on an electrodynamic shaker and linear power amplifier (ET-126A and PA-119; Labworks, Costa Mesa, CA).

Recording protocol. To confirm the validity of our method for isolating bilateral carotid sinus baroreceptor regions in 11 rats, we examined the relationship between carotid sinus pressure and aortic arch pressure. After a stabilization period during which both carotid sinus pressures were kept at 100 mmHg for 30 min, we began our recording protocol wherein both carotid sinus pressures were sequentially altered in 20-mmHg step increments from 60 to 180 mmHg and then in 20-mmHg decrements from 180 to 60 mmHg. Each step was maintained for 1 min. The same cycle of sequential changes in carotid sinus pressures was repeated five times over a 1-h period. The electrical signals of carotid sinus pressure and aortic arch pressure were first low-pass filtered with antialiasing filters having a cutoff frequency of 100 Hz (-3 dB) and an attenuation slope of -80 dB/octave (ASIP-0260L; Canopus, Kobe, Japan) and then digitized at a rate of 200 Hz by means of an analog-to-digital converter (AD12-16D98H; Contec, Osaka, Japan).

In Situ Isolation of Baroreceptor Area of Aortic Depressor Nerve

Surgical procedures. A midline incision was made in the neck and upper chest. The sternum was cut and the upper chest was opened. The sternomastoid and omohyoid muscles were cut. The aortic arch, innominate, right common carotid, subclavian, vertebral, and internal thoracic arteries were identified under the surgical operating microscope. The innominate artery was ligated at its root. A 10-cm-long polyethylene tubing (PE-50) was cannulated into the right common carotid artery at its middle portion. The tip of the polyethylene tubing was advanced and placed at the bifurcation of the innominate artery. The fluid-filled transducer and servocontrolled pump system were connected to the tubing. The right subclavian artery was ligated immediately proximal to its first branch, i.e., the vertebral or internal thoracic artery. These procedures made a completely watertight chamber of the bifurcating site of the innominate artery and of the proximal portion of the subclavian artery within 0.5 h from beginning to end (Fig. 2A).


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  		Fig. 2.   A: schematic illustration of in situ isolation of the baroreceptor region of the right aortic depressor nerve. Baroreceptors are located at the root of the right subclavian artery. B: original tracings of the pressure imposed on the in situ subclavian baroreceptors and of aortic arch pressure (AoP).

In a preliminary study, we confirmed that the pressure stimulation imposed on this vascularly isolated region evoked the functionally significant baroreflex control of aortic arch pressure in three rats. After we denervated bilateral carotid sinus regions and cut bilateral vagi and the left aortic depressor nerve, we imposed the pressure between 80 and 180 mmHg on the isolated region. As shown in Fig. 2B, aortic arch pressure responded baroreflexively.

Nerve recording. The right vagus and recurrent nerves were cut at the level of the subclavian artery, and the right stellate ganglion was removed. The right aortic depressor nerve was identified and cut at its junction with the superior laryngeal nerve (9) and was traced toward the bifurcation of the innominate artery under the microscope. The nerve was desheathed and placed on a pair of platinum-iridium wires. The recording site was immersed in a pool of mineral oil. Multifiber nerve activity was band-pass filtered between 150 and 3,000 Hz and amplified with a differential amplifier (JB-610J and AB-610J; Nihon Kohden, Tokyo, Japan). The envelope of multifiber nerve activity was generated through the use of full-wave rectifying and low-pass filtering equipment with a cutoff frequency of 50 Hz (-3 dB) and with an attenuation slope of -6 dB/octave.

Recording protocol. To confirm the validity of our method for isolating the in situ baroreceptor area of the aortic depressor nerve and studying the baroreceptor transduction, we investigated the relationship between the pressure imposed on the vascularly isolated region and aortic depressor nerve activity in nine rats. After a 30-min stabilization period during which the pressure in the vascularly isolated region was kept at 100 mmHg, the pressure was sequentially altered from 40 to 180 mmHg and back again in 20-mmHg steps. Each step was kept for 1 min. The same cycle of sequential pressure changes was repeated five times over a 70-min period. The electrical signals of the imposed pressure and the enveloped waveform of the aortic depressor nerve activity were low-pass filtered with the antialiasing filters and digitized at a rate of 200 Hz. Finally, we recorded the background noise for 10 min after the aortic depressor nerve was cut between the recording site and the baroreceptors.

Data Analysis

For purposes of data reduction and antialiasing, digitized data were resampled at 10 Hz after a 20-point moving average was applied. A preliminary study indicated that the response of aortic arch pressure to each pressure step imposed on bilateral carotid sinus baroreceptors and the response of right aortic depressor nerve activity to each pressure step imposed on subclavian baroreceptors reached steady state within 30 s (unpublished observation). Each steady-state value of the response, therefore, was obtained by the averaging of the latter 30-s values during each pressure step for 1 min. For each rat, aortic depressor nerve activity was normalized by the value at 180 mmHg after the background noise level averaged for 10 min was subtracted. Finally, the response of aortic arch pressure or aortic depressor nerve activity to the same level of input pressure was averaged for each rat.

To parametrically characterize the relationship between the input and output, we analyzed the data for each animal using a four-parameter logistic equation model (8)
<IT>y</IT> = <IT>p</IT><SUB>4</SUB> + <IT>p</IT><SUB>1</SUB>&cjs0823;  {1 + exp [ <IT>p</IT><SUB>2</SUB>(<IT>x</IT> − <IT>p</IT><SUB>3</SUB>)]} (1)
where y is output and x is input. The four parameters are defined as follows: p1 is the range of change in y (i.e., maximum minus minimum values of y), p2 is the coefficient for calculation of gain, p3 is the value of x corresponding to the midpoint over the range of y, and p4 is the minimum value of y. The instantaneous gain was also calculated from the first derivative of the logistic function, and the maximum gain is -p1 p2/4 at x = p3.

To determine threshold pressure for baroreceptors of the aortic depressor nerve, we analyzed the effect of the subclavian pressure on aortic depressor nerve activity by a mixed model of analysis of variance. A post hoc analysis for multiple comparisons was performed by a Scheffé's procedure. Differences were considered significant at P < 0.05.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Figure 3A shows a representative example of original tracings of carotid sinus pressure and aortic arch pressure during five cycles of sequential changes in carotid sinus pressure from 60 to 180 mmHg and back again. The response of aortic arch pressure to a given input appeared to be consistent and reproducible throughout the 1-h recording protocol. Neither vascularly isolated carotid sinus region leaked. The relationship between carotid sinus pressure and aortic arch pressure is illustrated in Fig. 3B. Similar results were obtained in all of the rats used. The results of the four-parameter logistic regression analysis of the carotid sinus baroreflex control of arterial pressure from 11 halothane-anesthetized rats are summarized in Table 1.


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  		Fig. 3.   A: original tracings of carotid sinus pressure (CSP) and AoP during 5 cycles of sequential changes in bilateral CSP from 60 to 180 mmHg and back again. Response of AoP to a given input appears to be consistent and reproducible throughout the 1-h recording protocol. B: graph showing relationship between CSP and AoP in A. bullet , Mean of values (open circle ) of responses to the same levels of input pressure during 5 cycles of sequential changes in bilateral CSP from 60 to 180 mmHg and back again. A 4-parameter logistic regression analysis estimated a maximum gain (Gmax) of -2.48 at CSP of 120 mmHg. y, Output; x, input; p1, range of change in y (i.e., maximum minus minimum values of y); p2, coefficient for calculation of gain; p3, value of x corresponding to midpoint over range of y; p4, minimum value of y. See METHODS for further explanation of the 4-parameter logistic regression analysis.

                              
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  		Table 1.   Four-parameter logistic regression analysis of the relationship between carotid sinus and aortic arch pressures in 11 rats

A representative example of original recordings of the pressure imposed on the in situ subclavian baroreceptors and the right aortic depressor nerve activity is shown in Fig. 4A. The nerve activity was normalized by the steady-state values at 180 mmHg. The steady-state responses appeared nearly saturated at 160 mmHg. The pressure threshold for evoking a steady-state response appeared to be ~80 mmHg. The relationship between the imposed pressure and aortic depressor nerve activity is illustrated in Fig. 4B. A multiple-comparison test with a Scheffé's procedure indicated a significant difference between the steady-state responses to subclavian pressures of 60 and 80 mmHg, while showing no significant difference between those of 40 and 60 mmHg. Table 2 shows the results of the four-parameter logistic regression analysis of the response of the in situ subclavian baroreceptors to pressure from nine rats.


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  		Fig. 4.   A: original recordings of the pressure imposed on the in situ subclavian baroreceptors and of right aortic depressor nerve (ADN) activity. ADN activity is normalized by the steady-state values at 180 mmHg. Response of ADN activity to a given input appears to be consistent and reproducible throughout the 70-min recording protocol. B: graph showing relationship between pressure imposed on the in situ subclavian baroreceptor and ADN activity in A. bullet , Mean of values (open circle ) of responses to the same levels of input pressure during 5 cycles of sequential changes in subclavian pressure from 40 to 180 mmHg and back again. A 4-parameter logistic regression analysis estimated a Gmax of 0.0223 arbitrary units (a.u.)/mmHg at 121 mmHg. See METHODS for explanation of 4-parameter logistic regression analysis.

                              
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  		Table 2.   Four-parameter logistic regression analysis of the relationship between subclavian pressure and aortic depressor nerve activity in 9 rats

Finally, we constructed the averaged curves of the steady-state responses of aortic arch pressure to carotid sinus pressure (Fig. 5A) and those of aortic depressor nerve activity to subclavian arterial pressure (Fig. 5B) from mean values for parameters p1-p4 shown in Tables 1 and 2. We also present the relationship between the instantaneous gain and the input pressure level. These results clearly reveal that the instantaneous gain of the carotid sinus baroreflex control of aortic arch pressure reached its peak at around the input pressure level where the line of identity intersected the logistic function curve. A nearly identical level of pressure also gave the maximum gain of the response of aortic depressor nerve to subclavian arterial pressure.


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  		Fig. 5.   Averaged results from 4-parameter logistic regression analyses. Logistic function curves were constructed from mean values for parameters p1-p4 shown in Tables 1 and 2. A: graph showing relationship between CSP and AoP (solid line) and relationship between CSP and instantaneous gain of the carotid sinus baroreflex control of AoP (dashed line). Dotted line shows line of identity of relationship between CSP and AoP. Line of identity intersects the logistic function curve at a CSP of 121 mmHg (open circle ). B: graph showing relationship between pressure and subclavian baroreceptor activity of ADN (solid line) and relationship between pressure and instantaneous baroreceptor gain (dashed line). See text for detailed explanation.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

Isolation of Carotid Sinus Baroreceptor Area

To isolate the carotid sinus of the rat, we found a commercially available product, ball bearings, to use as emboli. The ball bearing has a very smooth surface, and various sizes are available. These characteristics help the ball bearing smoothly lodge in the artery and make any special injector unnecessary. The following anatomic features of the internal carotid and pterygopalatine arteries are also important to successful embolization: 1) each artery enters its hole, the carotid canal or posterior lacerated foramen; 2) the sizes of the two arteries are similar; and 3) the sizes of the two holes are also similar. Therefore, if the external carotid artery is ligated at its origin, the two 0.8-mm-diameter ball bearings introduced into the common carotid artery will pass through the carotid sinus and never fail to wedge in the two arteries at the entrances to the skull. We have never failed to make a watertight chamber of the carotid sinus of the rat by our new method.

It should also be emphasized that our method does not need the manipulation of any structures above the bifurcation of the common carotid and that our reduction in surgical procedures significantly shortens the time needed for isolation. These advantages could minimize the damage to the baroreceptor and sinus nerve and keep the animal in a good experimental condition. The fact that the response of aortic arch pressure to a given input appeared to be consistent and reproducible throughout the 1-h recording protocol (Fig. 3A) leads us to conclude that our method is valid for isolating the carotid sinus baroreceptor region in the rat.

In Situ Isolation of Baroreceptor Area of Aortic Depressor Nerve

Recently we developed an in situ method for isolating the right subclavian baroreceptor area of the right aortic depressor nerve in rabbits (19). Our previous result indicated that the threshold of the baroreceptor for nonpulsatile pressure was very different from that shown in an ex vivo study by Angell-James (1). Because baroreceptors sense the vascular deformation induced by not only intravascular pressure but also a direct stretch of the wall, we speculated that the difference resulted from difficulties in the ex vivo preservation of the in situ normal configuration of the vasculature. The in vitro aortic arch-left aortic depressor nerve preparation for the study of baroreceptor transduction in rats developed by Brown and co-workers (4, 5) would also have a similar limitation. The present study estimated the pressure threshold for a steady-state response to be 80 mmHg, although Brown et al. (4) reported one of 104 mmHg. Our results are similar to the in situ data reported by DiBona and Sawin (7).

Baroreflex and Baroreceptor Gain

The present results shown in Fig. 5 suggest the following characteristics of baroreflex and baroreceptor function: 1) the input pressure level giving the maximum gain of the carotid sinus baroreflex control of aortic arch pressure is very close to the operating point for the feedback control system, i.e., the operating point would be a pressure where input pressure equaled output pressure on the logistic function curve showing the relationship between the two under open-loop conditions (8); and 2) the input pressure level is in good agreement with that corresponding to the midpoint of the operating range of subclavian baroreceptor activity. Our results concerning subclavian baroreceptor function are similar to the findings on carotid sinus baroreceptor function by Nosaka and Wang (15). Therefore, assuming that these two baroreceptors work similarly, the properties of the gain of the baroreflex control of arterial pressure can be explained in large part by the characteristics of the baroreceptor gain. Further investigation is needed, however, for clarifying the mechanisms of the baroreflex control of arterial pressure in rats.

Conclusions

We developed new methods for isolating the carotid sinus baroreceptor region by using ball bearings and for the in situ isolation of the baroreceptor area of the right aortic depressor nerve by ligation of the innominate, common carotid, and right subclavian arteries. These simple methods afford the advantages of requiring no special tools, needing no manipulation of the baroreceptor regions, requiring no extensive surgery, and consuming no long periods of time.

    ACKNOWLEDGEMENTS

We thank Tomoko Hino for helpful information on the manufacturer of ball bearings.

    FOOTNOTES

This study was supported by a grant-in-aid for Developmental Scientific Research (no. 09770051) from the Ministry of Education, Science, Sports, and Culture of Japan; by a grant for Encourage System of the Center of Excellence from the Science and Technology Agency of Japan; and by the Health Sciences Research Grant for Advanced Medical Technology (FY1997) from the Ministry of Health and Welfare of Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests: T. Sato, Dept. of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.

Received 3 February 1998; accepted in final form 8 September 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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Am J Physiol Heart Circ Physiol 276(1):H326-H332
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


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